Re-sensitizing ER-Alpha Mutant Breast Cancer Cells to Hormonal Therapy

摘要

ABSTRACT The majority of breast cancer cases are estrogen receptor (ERα)-positive. While hormonal therapy improves clinical outcomes for about half of patients with ERα-positive breast cancer, de novo or acquired resistance represents a significant clinical challenge. Among several underlying mechanisms, hot-spot point mutants of ERα are known to confer therapeutic resistance due to their estrogen-independent transcriptional activity. Thus, mitigating aberrant transcription activity of these ERα mutants holds promise for overcoming therapeutic resistance in treatment of ERα-positive breast cancer. As the second member of the ER family, ERβ is capable of interfering with ERα activity through heterodimerization and/or competing for common chromatin binding sites. This ERα-interfering function of ERβ could be utilized to overcome the activity of therapeutically resistant ERα mutants. However, clinical feasibility of this approach is vastly under-explored, as little is known about how ERα-interfering activity of ERβ is mobilized. Our preliminary work discovered a functionally important phosphotyrosine switch in ERβ. Specifically, we found that unphosphorylated ERβ is particularly potent in heterodimerization and functional interference with ERα. We therefore hypothesize that unphosphorylated ERβ in ERα-positive breast cancer can help overcome ERα mutant-mediated therapeutic resistance. We further envision that pharmacological agents that fine-tune the phosphotyrosine status of ERβ could be clinically useful in stimulating its ERα-interfering activity. We will test this novel hypothesis through two Specific Aims. First, we will use in vitro and patient- derived xenograft models to determine the impact of ERβ phosphorylation status on ERα-mediated therapeutic resistance. Second, we will use molecular and pharmacological tools to elucidate the mechanism by which ERβ phosphorylation status regulates the ERα/β crosstalk. The concept of overcoming therapeutic resistance by rallying a particular form of ERβ represents a novel concept. Furthermore, because the inhibitor of the upstream kinase for the phosphotyrosine switch is clinically available and ERβ-specific agonists are well tolerated in humans, our work provides multiple druggable targets for fine-tuning ERβ activities and imminent translatability for treating ERα-positive breast cancer. Our proposed study promises both conceptual and translational advances in understanding of how to overcome therapeutic resistance to hormonal therapy, a pressing clinical challenge in breast cancer treatment.